Submissions for variant NM_024334.3(TMEM43):c.742C>A (p.Leu248Met)

gnomAD frequency: 0.00004  dbSNP: rs780389237

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001183922	SCV001349770	uncertain significance	Cardiomyopathy	2023-04-21	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 248 of the TMEM43 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 8/281422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001244427	SCV001417647	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 248 of the TMEM43 protein (p.Leu248Met). This variant is present in population databases (rs780389237, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TMEM43-related conditions. ClinVar contains an entry for this variant (Variation ID: 923336). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001529347	SCV001996910	uncertain significance	not provided	2023-12-28	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics	RCV002379711	SCV002668507	benign	Cardiovascular phenotype	2023-10-26	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002505782	SCV002814366	uncertain significance	Arrhythmogenic right ventricular dysplasia 5; Emery-Dreifuss muscular dystrophy 7, autosomal dominant; Auditory neuropathy, autosomal dominant 3	2021-07-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001529347	SCV003799420	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing	The TMEM43 c.742C>A; p.Leu248Met variant (rs780389237), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 923336). This variant is reported in the non-Finnish European population with an overall allele frequency of 0.006% (8/128,976 alleles) in the Genome Aggregation Database. The leucine at codon 248 is moderately conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.181). Due to limited information, the clinical significance of the p.Leu248Met variant is uncertain at this time.
Molecular Genetics, Royal Melbourne Hospital	RCV001244427	SCV004812870	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2023-09-04	criteria provided, single submitter	clinical testing	This sequence change in TMEM43 is predicted to replace leucine with methionine at codon 248, p.(Leu248Met). The leucine residue is highly conserved (100 vertebrates, UCSC), and is located in the perinuclear space. There is a small physicochemical difference between leucine and methionine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.006% (8/128,976 alleles) in the European non-Finnish population. To our knowledge, this variant has not been previously reported in the relevant scientific literature or databases. Computational evidence predicts a benign effect for the missense substitution (REVEL = 0.181). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: BP4
All of Us Research Program, National Institutes of Health	RCV001244427	SCV004841554	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 248 of the TMEM43 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 8/281422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529347	SCV001742628	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529347	SCV001969919	likely benign	not provided		no assertion criteria provided	clinical testing